Category Archives: Ulcerative colitis

Ulcerative Colitis’ NKT Cells and Nanoparticle siRNA

Cobalt-graphene-nanoparticle
Nanoparticles may be a new way to transport active molecules to specific cells in IBD patients.
This week on TIBDI: Interleukin-13-producing NKT cells may be behind ulcerative colitis, and nanoparticle transport of CD98 small interfering RNAs may offer new treatment options for IBD.

An NKT Cell Antigen for Ulcerative Colitis

Ulcerative colitis (UC) is well known for its association with Th2 responses. More recently, it was found that IL-13-producing, Type II NKT cells accumulate in a rodent model of UC. Furthermore, these studies showed that IL-13 is cytotoxic for the epithelial cells and increases the killing activities of NKT cells. Dr. Ivan J Fuss of the National Institutes of Health continued this work in human UC patients. He found that the NKT cells accumulate in the lamina propria and when exposed to the self-antigen lyso-sulfate begin to secrete large amounts of IL-13 and upregulate IL-13Rα2 (IL-13 receptor). The authors speculate that these cells could be the main drivers of UC inflammation and that a key pathologic event in UC may be the abnormal expression of lyso-sulfate by gut epithelial cells in response to signals from microbiota.

Nanoparticles for the Treatment of IBD

Small interfering RNAs (siRNAs) offer the possibility of treating IBD by silencing disease-related genes. However, carriers are needed to bring these molecules to the cytoplasm of the correct cells. Dr. Bo Xiao of Georgia State University found success delivering CD98 siRNA to CD98+ gut cells by using orally administered nanoparticles coated with a targeting antibody and polyethylene glycol, which allows the particles to enter the mucus layer and reach the immune cells below. CD98 is part of the amino acid transporter LAT1, which amplifies integrin signaling and supports immune cell activation. The research team was able to successfully use their system to reduce the symptoms of two colitis models.

References

Insight: Fecal Microbiota Transplantation in Inflammatory Bowel Disease

Couple of Bacteria
Resetting the intestinal bacteria can lead to great benefits.
One of the most interesting and unique therapies that have come out of the microbiota revolution is the fecal microbiota transplant. Despite a certain “yuck” factor, interest in this technique grows especially as clinical trials and case studies with a number of diseases are proving successful. How does it work with inflammatory bowel disease (IBD)?

Intestinal Microbiota

The intestinal tract is the home to at least 1014 bacteria, which are members of hundreds of different species and strains. Even though most of us already knew that fecal matter consisted mainly of bacteria since we were children, this particular field of research wasn’t particularly popular until the last few years. The reason had more to do with a lack of tools than interest. It is only now that we have high-throughput screening techniques and computational software that can deal with the data such a study generates.

Now that we have these tools at our fingertips, it’s now known that the composition of the intestinal microflora plays a huge role in modulating health. Starting with the very first exposures during birth until old age, we now know that the intestinal microbiota influence the immune system, metabolism and even our mental well-being.

In IBD, the intestinal microbiota is altered. Patients have reduced numbers of bacteria from the phyla Firmicutes and Bacteroidetes and increased numbers from Actinobacteria and Proteobacteria. Although it isn’t known if these changes cause IBD, or if IBD is caused by an infectious agent, the possibility of finding a cure is enough to spur on studies involving FMT.

Fecal Microbiota Transplantation (FMT)

Quite simply, FMT involves the transfer of a fecal solution collected from a healthy donor into the intestinal tract of a recipient. Donors are usually family members, and they are screened for infections and other health issues. Fecal matter is usually mixed with water or saline and administered immediately either through a colonoscopy procedure or a duodenal infusion that requires a tube entering from the nose.

FMT is an extremely effective treatment for Clostridium difficile infections with cure rates of over 80%. In IBD, the results are not so clear cut. An initial study was done in 1988 with an ulcerative colitis (UC) patient that resulted in a cure. This success was followed in 2003 with six more patients. Nowadays, enough patients have been treated to give us an idea of how effective this treatment could be. It appears that approximately 63% of UC patients enter remission after FMT. Follow up studies indicate that benefits can be retained in the long-term for some patients.

FMT is less studied in Crohn’s disease (CD), and it appears to be less successful. However, there’s still plenty of room to improve this technique in the future. Moreover, there are several clinical studies; located in China, Beth Israel Deaconess Medical Center and Seattle Children’s Hospital; now recruiting patients to look specifically at the use of FMT in CD.

References

What’s Missing in Ulcerative Colitis and T Cell Derived Opioids

Met-enkephalin 1plx model 1
Enkephalin. T cells take away the pain with their own opioids.
Two important bacterial species are lost in ulcerative colitis patient microflora, genes behind bacterial colonization are discovered and T cells have a new role as the intestinal drug dealer.

Bacterial Colonization Genes Discovered

In the journal Nature this week, there is an article that describes bacterial genes that are needed for colonization in the colon. These genes, dubbed commensal colonization factors (ccf), are needed for the stabile colonization of bacteria within a host colon, the ability to nestle in mucus, and the control of population size. These genes, found so far in Bacteroides species, are activated by components found in the mucus, and lead the authors to believe that the colon may control populations of bacteria and their long-term stability by providing specific substrates as nutrients. For inflammatory bowel disease (IBD) patients this could lead to new insights about how to control the intestinal microflora and why IBD patient flora is different.

Missing Bacteria in Ulcerative Colitis

Initial studies have indicated that IBD patient intestinal microbiota are different than that of healthy individuals. However, more attention has been paid to Crohn’s disease (CD) than to ulcerative colitis (UC). Now, a Belgian team has addressed that issue in the journal, Gut. They have found that the changes in UC are different than that found in CD. Ulcerative colitis patients have significantly less Roseburia hominis and Faecalibacterium prausnitzii, and their reductions are indirectly correlated with disease activity. These bacteria are known for the production of butyrate, which functions as a nutrient and an immunomodulatory factor in the colon.

T Cells, the Local Opioid Supplier

A French study has found a new role for effector T cells in the gut during colitis: opioid producers. This study, accepted by Gastroenterology, demonstrates that murine T helper 1 and 17 cells produce enkephalin peptides. Enkephalin peptides are endogenous opioid receptor ligands. Using the T cell transfer model of colitis, they determined that T cells causing colitis simultaneously produce opioids. By combining the colitis model with opioid receptor blockers, they determined that these receptors were controlling visceral sensitivity, and therefore, the T cells were likely playing an analgesic function with their enkephalin secretion.

References

  • Boué, J., Basso, L., Cenac, N., Blanpied, C., Rolli-Derkinderen, M., Neunlist, M., et al. (2013). Accepted Manuscript. Gastroenterology, 1–36. doi:10.1053/j.gastro.2013.09.020
  • Lee, S. M., Donaldson, G. P., Mikulski, Z., Boyajian, S., Ley, K., & Mazmanian, S. K. (2013). Bacterial colonization factors control specificity and stability of the gut microbiota. Nature, 501(7467), 426–429. doi:10.1038/nature12447
  • Machiels, K., Joossens, M., Sabino, J., De Preter, V., Arijs, I., Eeckhaut, V., et al. (2013). A decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii defines dysbiosis in patients with ulcerative colitis. Gut. doi:10.1136/gutjnl-2013-304833

New Findings on the Brain-Gut Axis

Glosso
The vagus nerve’s connection with the spleen may play a role in IBD.
The brain-gut axis is receiving more attention as a possible target for modern inflammatory bowel disease (IBD) drugs. A recent publication shows an interesting vagus nerve-spleen axis role in colitis, while older publications indicate several other brain-gut associations in ulcerative colitis (UC) and with gut microbiota.

Vagus nerve-spleen axis in colitis

The vagus nerve is mainly responsible for communicating information from the visceral organs to the brain. It also is known to promote anti-inflammatory immune responses. In a study looking at the influence of the vagus nerve on murine colitis models, Ji et al. found that increasing centrally stimulating the vagus nerve led to decreased symptoms of murine colitis and that these effects were mediated mainly via release of acetylcholine in the spleen, which interacted with a7 nicotinic acetylcholine receptor (α7nAChR) on CD11c+ cells, lowering their activation state. In general, CD11c+ cells are considered to be antigen presenting cells, which open the door for brain control of the adaptive immune response. More information about the vagus nerve and immune regulation can be also be found in a recent review by Matteoli and Boeckxstaens in July’s issue of Gut.

Different Emotional Responses in Ulcerative Colitis

To answer the question if IBD patients have different brain responses, two years ago researchers performed brain scans on patients with ulcerative colitis. Agonstini et al. imaged brains from both patients and controls after exposing them to emotional visual stimuli. It was found that the UC patients were less sensitive to positive emotional stimuli. This may play a role in why IBD sufferers have an increased incidence of depression.

Intestinal Bacteria Influence Brain Activity

In a more recent study with only healthy women, Tillisch et al. looked at the effects of the consumption of fermented milk on brain function. After four weeks of daily probiotics, changes were observed in the areas of the brain associated with emotional processing and sensation. On a practical level, this could mean that the women were more resistant to pain and stress. However, a larger study would need to be performed to be certain.

What’s your opinion regarding the brain’s involvement with IBD or do you have any personal experiences that show a link? Please share in the comment section below.

References:

Agostini, A., Filippini, N., Cevolani, D., Agati, R., Leoni, C., Tambasco, R., et al. (2011). Brain functional changes in patients with ulcerative colitis. Inflammatory Bowel Diseases, 17(8), 1769–1777. doi:10.1002/ibd.21549

Ji, H., Rabbi, M. F., Labis, B., Pavlov, V. A., Tracey, K. J., & Ghia, J. E. (2013). Central cholinergic activation of a vagus nerve-to-spleen circuit alleviates experimental colitis. Mucosal Immunology, 1–13. doi:10.1038/mi.2013.52

Matteoli, G., & Boeckxstaens, G. E. (2013). The vagal innervation of the gut and immune homeostasis. Gut, 62(8), 1214–1222. doi:10.1136/gutjnl-2012-302550

Tillisch, K., Labus, J., Kilpatrick, L., Jiang, Z., Stains, J., Ebrat, B., et al. (2013). Consumption of Fermented Milk Product With Probiotic Modulates Brain Activity. Gastroenterology, 144(7), 1394–1401.e4. doi:10.1053/j.gastro.2013.02.043

 

 

The IBD Microbiota: New Therapeutic Target?

microbiota timelineThe latest publication of Nature Immunology focuses on microbiota. With four excellent reviews, they cover a wide-range of microbiota-related topics from pattern-recognition receptors in the fruit-fly to the microbiota-nutrition-immune triangle. Does this new field of study offer any hope for inflammatory bowel disease (IBD)?

It’s important to realize that the microbiota inside one’s gut isn’t just bacteria. In actuality, it also has representatives from the Archaea (ancient bacteria) and Eukarya domains. Examples of Eukarya are fungi and parasites. Together, this thriving community is called the “microbiome,” and it is highly diverse containing between 1000-36,000 species of bacteria. Most scientists are currently focusing on the bacterial inhabitants.

Using high-throughput 16S small-subunit ribosomal sequencing to identify bacterial species, scientists can now identify changes in the microbiome of IBD patients. In 2007, one of the first studies was published in PNAS using this technique on surgically isolated gut wall bacteria. It revealed that in IBD many bacteria from the phyla Firmicutes and Bacteroidetes were depleted while a variety of Actinobacteria and Proteobacteria were more abundant. The study also revealed that abnormal microbiotas were also significantly correlated with abscesses in Crohn’s disease (CD).

These studies fail to tell us, however, if these changes are cause or consequence. This explains why studies with probiotics, fecal transplantation and diet are now so popular. From these studies, it appears that modulating the IBD microbiota can influence the disease, especially in ulcerative colitis (UC) patients. The probiotic formulation VSL#3 is now recognized as a treatment in ulcerative colitis. Fecal transplantation, where feces from healthy donors are transferred via an enema to patients, has also shown success. Some UC patients have maintained remission up to 13 years with fecal transplantation alone. And, finally, diet is highly impactful on the intestinal flora, and it is well known that enteral nutrition can induce remission in IBD.

Interestingly, all of these manipulations of IBD microbiota need to be maintained. Probiotics need to be taken daily, fecal transplants repeated, and diets followed to prevent relapses. This would suggest that there is still something about the IBD patient’s intestinal microenvironment that’s still promoting disease. The fecal transplantation study particularly supports this idea seeing that the patients are more or less sterile before getting their new donor microbiota.

Genome wide association scans suggest a reason. The major mutations associated with IBD are in pathways that are involved with dealing with bacteria. One of the most well known genes found to be mutated in IBD is NOD2. NOD2 recognizes muramyl dipeptide, a bacterial-associated molecule and activates the pro-inflammatory transcription factor, NF-κB. In mice, loss of Nod2 reduces the expression of anti-microbial peptides in the terminal ileum. One could imagine that in patients with this mutation, there would be defects in regulating the microbiota.

In my last post, I described research using a stress-induced model of intestinal inflammation. There they showed that stress could induce changes in the immune system, which then led to changes in the microbiota and intestinal inflammation. Interestingly, changes could happen in the other direction. Co-housed, healthy mice were given the same disease (and immunological changes) just by eating the stressed mice’s feces. This study highlights that there is a bi-directional relationship between our microbiota and us. Could this mean that the best treatments are also the one’s that target both our flora and our immune systems?

Please tell me what you think? Leave a comment down below!

References:

Albenberg, L. G., Lewis, J. D., & Wu, G. D. (2012). Food and the gut microbiota in inflammatory bowel diseases. Current opinion in gastroenterology, 28(4), 314–320.

Aroniadis, O. C., & Brandt, L. J. (2013). Fecal microbiota transplantation. Current opinion in gastroenterology, 29(1), 79–84.

Brown, E. M., Sadarangani, M., & Finlay, B. B. (2013). The role of the immune system in governing host-microbe interactions in the intestine. Nature immunology, 14(7), 660–667.

Frank, D. N. D., Amand, A. L. A. S., Feldman, R. A. R., Boedeker, E. C. E., Harpaz, N. N., & Pace, N. R. N. (2007). Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. PNAS, 104(34), 13780–13785.

VSL#3®, The Living Shield™ – Why VSL#3®?, accessed June 28, 2013